A long standing goal of immunogenetics has been to understand the genetic basis of antibody diversity and responsiveness, to understand both the mechanisms through which the apparently limitless variety of antibody sequences are created and the reasons these mechanisms are used. This knowledge may enable the manipulation of the antibody response - positively, to enhance vaccine response and efficacy, negatively, to dampen and suppress autoantibody or anti-organ graft responses. Among other possibilities a thorough understanding of the structural range of combining sites encoded in the genetic repertoire should lead to a rational and accelerated strategy for vaccine development. This project will completely define and catalogue the mouse immunoglobulin heavy chain (Igh) locus in two strains. This will be done by isolating the entire locus as overlapping clones in Yeast and Bacterial Artificial Chromosomes (YACs and BACs) from two mouse strains. All mouse Vh genes will be cloned and sequenced to create a complete directory of the mouse germline repertoire for two quite different haplotypes. These will be compared among themselves and with the human Vh gene directory to identify Vh genes that have important protective or other functions, to identify noncoding regulatory structures and to characterize the forces shaping the evolution of antibody genes.